We are investigating the role of tumor suppressor genes in the pathogenesis of human cancer. Our recent findings are as follows: 1) We recently analyzed the expression of the RB tumor suppressor protein in over 180 samples of lung cancer of differing histologic type. This work defines a striking contrast in the incidence of RB inactivation in these different types of lung tumors and has been instrumental in allowing the recognition that there is an inverse relationship between RB inactivation and small homozygous deletions within the p16/MTS cyclin dependent kinase (CDK) inhibitor gene. This is a potentially important observation that suggests a general role for RB/p16 tumor suppressor pathways in a wide range of cancers. 2) We have characterized a unique class of RB mutant isolated from a family with incomplete penetrance of familial retinoblastoma. This mutant expresses partial inactivation with normal phosphorylation but defective protein "pocket" binding. This work was the first to propose a general mechanism for incomplete penetrance and/or spontaneous tumor regression seen in this syndrome. In addition, we are testing this mutant (as well as our previously identified mutants) as substrates for cdk gene products to define kinase partners for RB phosphorylation. 3) We are studying the interaction of the RB protein with a family of cellular binding proteins that are believed to modulate RB tumor suppressor activity. Using full-length cDNA clones and antisera raised in our laboratory, we have characterized the properties of the cellular retinoblastoma-binding protein 2 (RBP2) gene product We have demonstrated that this protein encodes multifunctional domains that resemble several properties of the E1A transforming virus. We are also working to identify new tumor suppressor binding proteins to define their functional roles and to determine whether they are also targets for mutations in human cancer. 4) We have studying the properties of a novel member of the human HSP7O protein chaperone gene isolated in our laboratory. In addition, we have recently identified the human chromosome localization of this gene are investigating whether this gene maps to a human disease locus.